Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway

Tareq Hossan; Sankari Nagarajan; Simon J. Baumgart; Wanhua Xie; Roberto Tirado Magallanes; Céline Hernandez; Pierre-marie Chiaroni; Daniela Indenbirken; Melanie Spitzner; Morgane Thomas-chollier; Marian Grade; Denis Thieffry; Adam Grundhoff; Florian Wegwitz; Steven A. Johnsen

doi:10.1002/stem.v34.5

Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway

Tareq Hossan, Sankari Nagarajan, Simon J. Baumgart, Wanhua Xie, Roberto Tirado Magallanes, Céline Hernandez, Pierre-marie Chiaroni, Daniela Indenbirken, Melanie Spitzner, Morgane Thomas-chollier, Marian Grade, Denis Thieffry, Adam Grundhoff, Florian Wegwitz, Steven A. Johnsen

Division of Molecular & Cellular Function (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Cellular differentiation is accompanied by dramatic changes in chromatin structure which direct the activation of lineage‐specific transcriptional programs. Structure‐specific recognition protein‐1 (SSRP1) is a histone chaperone which is important for chromatin‐associated processes such as transcription, DNA replication and repair. Since the function of SSRP1 during cell differentiation remains unclear, we investigated its potential role in controlling lineage determination. Depletion of SSRP1 in human mesenchymal stem cells elicited lineage‐specific effects by increasing expression of adipocyte‐specific genes and decreasing the expression of osteoblast‐specific genes. Consistent with a role in controlling lineage specification, transcriptome‐wide RNA‐sequencing following SSRP1 depletion and the induction of osteoblast differentiation revealed a specific decrease in the expression of genes involved in biological processes related to osteoblast differentiation. Importantly, we observed a specific downregulation of target genes of the canonical Wnt signaling pathway, which was accompanied by decreased nuclear localization of active β‐catenin. Together our data uncover a previously unknown role for SSRP1 in promoting the activation of the Wnt signaling pathway activity during cellular differentiation. Stem Cells 2016;34:1369–1376

Significance Statement
Epigenetic regulation plays an essential role in defining lineage‐specific gene expression patterns. We investigated the function of the histone chaperone SSRP1 during cellular differentiation and demonstrate its essential function in specifically directing multipotent mesenchymal stem cell differentiation to the osteoblast lineage via regulation of Wnt signaling. We thereby provide the first evidence of a lineage‐specific role of SSRP1 during cellular differentiation and uncover molecular insights into its function, which may serve as a basis for future clinical application of small molecule modulators of its activity for the treatment of aging‐related osteoporosis and other diseases associated with altered Wnt signaling.

Original language	English
Pages (from-to)	1369-1376
Journal	Stem Cells
Volume	34
Issue number	5
DOIs	https://doi.org/10.1002/stem.v34.5
Publication status	Published - 1 May 2016

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Hossan, T., Nagarajan, S., Baumgart, S. J., Xie, W., Magallanes, R. T., Hernandez, C., Chiaroni, P., Indenbirken, D., Spitzner, M., Thomas-chollier, M., Grade, M., Thieffry, D., Grundhoff, A., Wegwitz, F., & Johnsen, S. A. (2016). Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway. Stem Cells, 34(5), 1369-1376. https://doi.org/10.1002/stem.v34.5

@article{6c4511acc46349458fb8b35659e63eaf,

title = "Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway",

abstract = "Cellular differentiation is accompanied by dramatic changes in chromatin structure which direct the activation of lineage‐specific transcriptional programs. Structure‐specific recognition protein‐1 (SSRP1) is a histone chaperone which is important for chromatin‐associated processes such as transcription, DNA replication and repair. Since the function of SSRP1 during cell differentiation remains unclear, we investigated its potential role in controlling lineage determination. Depletion of SSRP1 in human mesenchymal stem cells elicited lineage‐specific effects by increasing expression of adipocyte‐specific genes and decreasing the expression of osteoblast‐specific genes. Consistent with a role in controlling lineage specification, transcriptome‐wide RNA‐sequencing following SSRP1 depletion and the induction of osteoblast differentiation revealed a specific decrease in the expression of genes involved in biological processes related to osteoblast differentiation. Importantly, we observed a specific downregulation of target genes of the canonical Wnt signaling pathway, which was accompanied by decreased nuclear localization of active β‐catenin. Together our data uncover a previously unknown role for SSRP1 in promoting the activation of the Wnt signaling pathway activity during cellular differentiation. Stem Cells 2016;34:1369–1376Significance StatementEpigenetic regulation plays an essential role in defining lineage‐specific gene expression patterns. We investigated the function of the histone chaperone SSRP1 during cellular differentiation and demonstrate its essential function in specifically directing multipotent mesenchymal stem cell differentiation to the osteoblast lineage via regulation of Wnt signaling. We thereby provide the first evidence of a lineage‐specific role of SSRP1 during cellular differentiation and uncover molecular insights into its function, which may serve as a basis for future clinical application of small molecule modulators of its activity for the treatment of aging‐related osteoporosis and other diseases associated with altered Wnt signaling.",

author = "Tareq Hossan and Sankari Nagarajan and Baumgart, {Simon J.} and Wanhua Xie and Magallanes, {Roberto Tirado} and C{\'e}line Hernandez and Pierre-marie Chiaroni and Daniela Indenbirken and Melanie Spitzner and Morgane Thomas-chollier and Marian Grade and Denis Thieffry and Adam Grundhoff and Florian Wegwitz and Johnsen, {Steven A.}",

year = "2016",

month = may,

day = "1",

doi = "10.1002/stem.v34.5",

language = "English",

volume = "34",

pages = "1369--1376",

journal = "Stem Cells",

issn = "1066-5099",

publisher = "AlphaMed Press",

number = "5",

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Hossan, T, Nagarajan, S, Baumgart, SJ, Xie, W, Magallanes, RT, Hernandez, C, Chiaroni, P, Indenbirken, D, Spitzner, M, Thomas-chollier, M, Grade, M, Thieffry, D, Grundhoff, A, Wegwitz, F & Johnsen, SA 2016, 'Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway', Stem Cells, vol. 34, no. 5, pp. 1369-1376. https://doi.org/10.1002/stem.v34.5

Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway. / Hossan, Tareq; Nagarajan, Sankari; Baumgart, Simon J. et al.
In: Stem Cells, Vol. 34, No. 5, 01.05.2016, p. 1369-1376.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation

T2 - SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway

AU - Hossan, Tareq

AU - Nagarajan, Sankari

AU - Baumgart, Simon J.

AU - Xie, Wanhua

AU - Magallanes, Roberto Tirado

AU - Hernandez, Céline

AU - Chiaroni, Pierre-marie

AU - Indenbirken, Daniela

AU - Spitzner, Melanie

AU - Thomas-chollier, Morgane

AU - Grade, Marian

AU - Thieffry, Denis

AU - Grundhoff, Adam

AU - Wegwitz, Florian

AU - Johnsen, Steven A.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Cellular differentiation is accompanied by dramatic changes in chromatin structure which direct the activation of lineage‐specific transcriptional programs. Structure‐specific recognition protein‐1 (SSRP1) is a histone chaperone which is important for chromatin‐associated processes such as transcription, DNA replication and repair. Since the function of SSRP1 during cell differentiation remains unclear, we investigated its potential role in controlling lineage determination. Depletion of SSRP1 in human mesenchymal stem cells elicited lineage‐specific effects by increasing expression of adipocyte‐specific genes and decreasing the expression of osteoblast‐specific genes. Consistent with a role in controlling lineage specification, transcriptome‐wide RNA‐sequencing following SSRP1 depletion and the induction of osteoblast differentiation revealed a specific decrease in the expression of genes involved in biological processes related to osteoblast differentiation. Importantly, we observed a specific downregulation of target genes of the canonical Wnt signaling pathway, which was accompanied by decreased nuclear localization of active β‐catenin. Together our data uncover a previously unknown role for SSRP1 in promoting the activation of the Wnt signaling pathway activity during cellular differentiation. Stem Cells 2016;34:1369–1376Significance StatementEpigenetic regulation plays an essential role in defining lineage‐specific gene expression patterns. We investigated the function of the histone chaperone SSRP1 during cellular differentiation and demonstrate its essential function in specifically directing multipotent mesenchymal stem cell differentiation to the osteoblast lineage via regulation of Wnt signaling. We thereby provide the first evidence of a lineage‐specific role of SSRP1 during cellular differentiation and uncover molecular insights into its function, which may serve as a basis for future clinical application of small molecule modulators of its activity for the treatment of aging‐related osteoporosis and other diseases associated with altered Wnt signaling.

AB - Cellular differentiation is accompanied by dramatic changes in chromatin structure which direct the activation of lineage‐specific transcriptional programs. Structure‐specific recognition protein‐1 (SSRP1) is a histone chaperone which is important for chromatin‐associated processes such as transcription, DNA replication and repair. Since the function of SSRP1 during cell differentiation remains unclear, we investigated its potential role in controlling lineage determination. Depletion of SSRP1 in human mesenchymal stem cells elicited lineage‐specific effects by increasing expression of adipocyte‐specific genes and decreasing the expression of osteoblast‐specific genes. Consistent with a role in controlling lineage specification, transcriptome‐wide RNA‐sequencing following SSRP1 depletion and the induction of osteoblast differentiation revealed a specific decrease in the expression of genes involved in biological processes related to osteoblast differentiation. Importantly, we observed a specific downregulation of target genes of the canonical Wnt signaling pathway, which was accompanied by decreased nuclear localization of active β‐catenin. Together our data uncover a previously unknown role for SSRP1 in promoting the activation of the Wnt signaling pathway activity during cellular differentiation. Stem Cells 2016;34:1369–1376Significance StatementEpigenetic regulation plays an essential role in defining lineage‐specific gene expression patterns. We investigated the function of the histone chaperone SSRP1 during cellular differentiation and demonstrate its essential function in specifically directing multipotent mesenchymal stem cell differentiation to the osteoblast lineage via regulation of Wnt signaling. We thereby provide the first evidence of a lineage‐specific role of SSRP1 during cellular differentiation and uncover molecular insights into its function, which may serve as a basis for future clinical application of small molecule modulators of its activity for the treatment of aging‐related osteoporosis and other diseases associated with altered Wnt signaling.

U2 - 10.1002/stem.v34.5

DO - 10.1002/stem.v34.5

M3 - Article

SN - 1066-5099

VL - 34

SP - 1369

EP - 1376

JO - Stem Cells

JF - Stem Cells

IS - 5

ER -

Histone Chaperone SSRP1 is Essential for Wnt Signaling Pathway Activity During Osteoblast Differentiation: SSSRP1 regulates osteoblast differentiation through Wnt-signaling pathway

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